tbuckley/cabot-search huggingface dataset:
In Situ Enzymatic Reaction Generates Magnesium‐Based Mineralized Microspheres with Superior Bioactivity for Enhanced Bone Regeneration
Authors: Zhuyun Cai, Xiaohao Liu, Miao Hu, Yichen Meng, Jianquan Zhao, Yixuan Tan, Xiong Luo, Ce Wang, Jun Ma, Zhongyi Sun, Yingying Jiang, Bingqiang Lu, Rui Gao, Feng Chen, Xuhui Zhou
Journal: Advanced Healthcare Materials (2023)

Bone is a naturally mineralized tissue with a remarkable hierarchical structure, and the treatment of bone defects remains challenging. Microspheres with facile features of controllable size, diverse morphologies, and specific functions display amazing potentials for bone regeneration. Herein, inspired by natural biomineralization, a novel enzyme-catalyzed reaction is reported to prepare magnesium-based mineralized microspheres. First, silk fibroin methacryloyl (SilMA) microspheres are prepared using a combination of microfluidics and photo-crosslinking. Then, the alkaline phosphatase (ALP)-catalyzed hydrolysis of adenosine triphosphate (ATP) is successfully used to induce the formation of spherical magnesium phosphate (MgP) in the SilMA microspheres. These SilMA@MgP microspheres display uniform size, rough surface structure, good degradability, and sustained Mg2+ release properties. Moreover, the in vitro studies demonstrate the high bioactivities of SilMA@MgP microspehres in promoting the proliferation, migration, and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). Transcriptomic analysis shows that the osteoinductivity of SilMA@MgP microspheres may be related to the activation of the PI3K/Akt signaling pathway. Finally, the bone regeneration enhancement units (BREUs) are designed and constructed by inoculating BMSCs onto SilMA@MgP microspheres. In summary, this study demonstrates a new biomineralization strategy for designing biomimetic bone repair materials with defined structures and combination functions.
A Dual Heat Shock Protein Down‐Regulation Strategy Using PDA/Cu/ICG/R Controlled by NIR “Switch” Enhances Mild‐Photothermal Therapy Effect
Authors: Xin Ding, Tianyu Wang, Shiwei Bai, Mian Yang, Na Peng, Tao Qiu, Yi Liu
Journal: Advanced Healthcare Materials (2023)

The purpose of this study is to down-regulate heat shock proteins and improve the mild photothermal therapy (mild-PTT) effect of polydopamine (PDA) by preparing the nanosystem of Cu2+ and indocyanine green (ICG)-loaded PDA nanospheres with surface modification of integrin-targeted cyclic peptide (cRGD) (PDA/Cu/ICG/R), which can limit ATP synthesis through the double mitochondrial destruction pathway. In vitro and in vivo experiments using PDA/Cu/ICG/R irradiated with an NIR laser demonstrate that when NIR is "OFF," Cu2+ can undergo Fenton-like reaction in tumor cells, producing a large amount of hydroxyl radicals (·OH), which leads to oxidative stress in cells. This oxidative stress can cause mitochondrial oxidative phosphorylation dysfunction, resulting in limited ATP synthesis. When NIR is "ON," mild-PTT can accelerate Cu2+ to produce ·OH. Simultaneously, NIR can activate ICG to produce reactive oxygen species (ROS) storm, amplify intracellular oxidative stress, and continuously damage mitochondria. The biodegradability of PDA greatly reduces the risk of toxicity caused by long-term retention of PDA/Cu/ICG/R in organisms. Finally, the improvement of the mild-PTT effect of PDA is successfully achieved through the double mitochondrial destruction pathway of Cu2+ and ICG controlled by NIR "switch."
Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of gynecologic cancer
Authors: Mary L Disis, Sarah F Adams, Jyoti Bajpai, Marcus O Butler, Tyler Curiel, Shelley A Dodt, Laura Doherty, Leisha A Emens, Claire F Friedman, Margaret Gatti-Mays, Melissa A Geller, Amir Jazaeri, Veena S John, Katherine C Kurnit, John B Liao, Haider Mahdi, Anne Mills, Emese Zsiros, Kunle Odunsi
Journal: Journal for ImmunoTherapy of Cancer (2023)

Advanced gynecologic cancers have historically lacked effective treatment options. Recently, immune checkpoint inhibitors (ICIs) have been approved by the US Food and Drug Administration for the treatment of cervical cancer and endometrial cancer, offering durable responses for some patients. In addition, many immunotherapy strategies are under investigation for the treatment of earlier stages of disease or in other gynecologic cancers, such as ovarian cancer and rare gynecologic tumors. While the integration of ICIs into the standard of care has improved outcomes for patients, their use requires a nuanced understanding of biomarker testing, treatment selection, patient selection, response evaluation and surveillance, and patient quality of life considerations, among other topics. To address this need for guidance, the Society for Immunotherapy of Cancer (SITC) convened a multidisciplinary panel of experts to develop a clinical practice guideline. The Expert Panel drew on the published literature as well as their own clinical experience to develop evidence- and consensus-based recommendations to provide guidance to cancer care professionals treating patients with gynecologic cancer.
Abstract 6634: Digital and spacial characterization of PD-L1 expression and IVD assay performance in the immune landscape of head and neck squamous cell carcinoma: A multimodal approach
Authors: Clara Troccoli, Lauren Matelski, Adam Beharry, Vanessa Ly, Morgan Wambaugh, Melanie Amen, Will Paces, Geoffrey Metcalf, Roberto Gianani, Tom Turi
Journal: Cancer Research (2023)

Abstract The anti-PD-L1 antibody (22C3) is used as a companion diagnostic for successful checkpoint inhibitor therapy in head and neck squamous cell carcinoma. The positive predictive value of this assay, however, is less than ideal as a high PD-L1 score does not necessarily associate with a good response, and a good response may be seen with a low or negative PD-L1 score. In principle, this could be due to lack of accuracy and/or precision of the assay, as well as biological factors, such as variable expression across tumor cells and interacting immune cells. In this study, we describe a digital image analysis algorithm to address assay-related problems and improve both accuracy and precision, as well as improve identification of PD-L1 expression in differing cell populations of the tumor microenvironment. In addition, we propose a panel of assays that in aggregate might reveal inherent heterogeneity among cases with similar PD-L1 score and thus provide vital context underlying the efficacy of checkpoint inhibitors in the clinic. Here we show that applying novel machine-learning based digital image analysis to multiplex assays together with digital scoring of PD-L1 provides an accurate and precise assessment of the real-world tumor milieu that we hypothesize will help establish the immunophenotypes that inform therapeutic efficacy of checkpoint inhibitors. We have additionally interrogated whether expression of PD-L1 in these groups are consistent with known molecular patterns assayed using novel methodologies, such as high-plex digital spatial transcriptomics through the nanoString GeoMx Digital Spatial Profiler (DSP) platform and assessed the ability of the different digital platforms to provide concordant data relating to real-world expression patterns of PD-L1 and associated biomarkers. Thus, our results point to the importance of robust methodologies, used in combination, to evaluate complex tumor immune landscapes and the advantages of digital analyses to provide accurate and precise clinical contexts for better patient outcomes. Citation Format: Clara Troccoli, Lauren Matelski, Adam Beharry, Vanessa Ly, Morgan Wambaugh, Melanie Amen, Will Paces, Geoffrey Metcalf, Roberto Gianani, Tom Turi. Digital and spacial characterization of PD-L1 expression and IVD assay performance in the immune landscape of head and neck squamous cell carcinoma: A multimodal approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6634.
Abstract 4743: Wnt/beta-catenin mediated epigenetic modifications drive age-dependent oral squamous cell carcinoma evolution
Authors: Emily R. Fisher, Anthony Spinella, Nina C. Hardy, Xaralabos Varelas, Manish Bais, Maria A. Kukuruzinska
Journal: Cancer Research (2023)

Abstract Oral Squamous Cell Carcinoma (OSCC) is a devastating disease associated with high morbidity, poor survival, and few therapeutic options. This malignancy is driven, in part, by epigenetic reprogramming of the chromatin landscape directed by β-catenin in complex with CREB-binding protein (CBP) and mixed lineage leukemia methyltransferase 1 (MLL1). The β-catenin/CBP/MLL1 complex promotes an open chromatin structure by enabling transcription of genes associated with cell plasticity, including cancer stem cells and cells with partial EMT (p-EMT) phenotypes. Growing evidence indicates that cell plasticity and cellular senescence are integral processes shared by cancer and aging. Given that the median age of OSCC diagnosis is 66 years, it is likely that aging promotes OSCC evolution to advanced disease. To examine the effects of aging on OSCC evolution, we adapted a syngeneic mouse model of tobacco-associated oral carcinogenesis. This model utilizes a mouse cell line, 4MOSC1, derived from 4-nitroquinoline-1 oxide- (4NQO)-induced tongue tumor which, when implanted into mouse tongues, generates tumors that recapitulate human OSCC mutanome. The growth of 4MOSC1 derived orthotopic tumors was studied in 6- and 80-week-old mice. Tumors were allowed to develop for 18 days, after which they were harvested and processed for single cell RNA sequencing, histopathology and immunofluorescence (IF) analyses. Results showed that tumors grew at a faster rate and to a greater overall size in old mice compared to their young cohorts. OSCC harvested from the old mice displayed statistically significant reduction in membranous E-cadherin concomitant with increased Cbp and H3K4me3 abundance, suggesting an age-associated upregulation of β-catenin/Cbp/Mll1 epigenetic activity. Increased expression of Bmi1, keratin 14, and podoplanin supported increased cell plasticity in OSCC from aged mice. Further, these tumors exhibited augmented cellular senescence, as judged by the disruption of lamin B1-associated nuclear membrane integrity, and by an increased cell population with markers of senescence from single cell sequencing analyses. These data suggest that aging is associated with increased β-catenin/Cbp/Mll1 epigenetic signaling, cell plasticity and cellular senescence, which collectively contribute to the evolution of OSCC. Citation Format: Emily R. Fisher, Anthony Spinella, Nina C. Hardy, Xaralabos Varelas, Manish Bais, Maria A. Kukuruzinska. Wnt/beta-catenin mediated epigenetic modifications drive age-dependent oral squamous cell carcinoma evolution. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4743.
Abstract 5824: Human ovarian cancer cell seeding density as a mechanism of cisplatin resistance associated with expression of anti-apoptotic and autophagy proteins
Authors: Thomas W. Brown, Ujwal Punyamurtula, Wafik S. El-Deiry
Journal: Cancer Research (2023)

Abstract Drug effects may vary depending on cancer cell density. We investigated discrepancies in phenotypes for high density and low-density cultured cancer cells and elucidated relevant variables that influence them. We assessed chemosensitivity as a function of tumor cell density by plating TOV-21G and OVMANA ovarian cancer cell lines in 96-well plates at various seeding densities per well and treated them with various concentrations of cisplatin. CellTiterGlo assays were performed at 72 hours of treatment to determine cisplatin dose response curves. We used ethidium homodimer fluorescence staining and imaging to quantify extent of cell death at differing cell densities of TOV-21G and OVMANA cells treated with cisplatin for 48 and 72hours in 48-well plates. We performed western blot analyses of apoptotic and autophagy proteins from TOV-21G and OVMANA cells that were seeded at high and low cell densities in 24-wellplates. TOV-21G and OVMANA cells plated at higher cell seeding densities displayed less cisplatin sensitivity than TOV-21G and OVMANA cells plated at lower seeding densities, as shown by cisplatin dose response curves. Ethidium homodimer staining of TOV-21G and OVMANA cells treated with cisplatin revealed that cells seeded at lower densities experience a greater amount of cell death that cells seeded at higher densities. Western blot analyses showed that high density TOV-21G cells may express greater amounts of BCL2 and c-FLIP and lower amounts of p62 and NOXA compared to low density cells when normalized for protein expression. Similarly, high density OVMANA cells express greater amounts of c-FLIP andBCL2 and lower amounts of NOXA compared to low density cells when normalized for protein expression. Our experiments reveal that human ovarian cancer cells display different phenotypic changes depending on cell density, causing higher density cells to require increased cisplatin to achieve the same level of effect seen in lower density cells. Ovarian cancer cell resistance to cisplatin is associated with alterations in autophagy and anti-apoptotic protein expression at high cell seeding density. These alterations may also affect chemosensitivity in vivo in settings of differential tumor density, such as single circulating tumor cells compared to clumps of tumor cells, and other settings, such as metastasis. Citation Format: Thomas W. Brown, Ujwal Punyamurtula, Wafik S. El-Deiry. Human ovarian cancer cell seeding density as a mechanism of cisplatin resistance associated with expression of anti-apoptotic and autophagy proteins. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5824.
Abstract 5509: The PI3K inhibitor Paxalisib combines synergistically with the MEK inhibitor Mirdametinib to target atypical teratoid/rhabdoid tumors
Authors: Kristen J. Malebranche, Tyler Findlay, Anupa Geethadevi, Charles Eberhart, Eric Raabe, Jeffrey Rubens
Journal: Cancer Research (2023)

Abstract Atypical teratoid/rhabdoid tumors (AT/RT) are aggressive pediatric brain tumors and the most common malignant brain tumors of infancy. The four-year event-free survival rate is only 37%. For patients with relapsed AT/RT there are limited treatment options, but precision therapies may help improve survival for patients with this deadly disease. We have previously identified strong activation of the PI3K-AKT-mTOR (mTOR) signaling pathways in AT/RT. Paxalisib is a highly brain-penetrant PI3K inhibitor acting upstream of mTOR. We find that Paxalisib slows tumor growth in orthotopic xenograft models of AT/RT and extends median survival from 40 to 54 days (p=0.001, log-rank test). RNASeq after mTOR pathway inhibition identifies reflexive activation of the RAS-RAF-MEK-ERK (MAPK) pathway as a possible mechanism of therapy resistance (KEGG pathway analysis). The RAS-RAF-MEK-ERK (MAPK) pathway plays a pivotal role in regulating cell growth and survival and activation of the pathway contributes to the aggressive growth of numerous cancers. Mirdametinib is a small, allosteric MEK inhibitor currently used in clinical trials for both pediatric low- and high-grade gliomas (PD0325901). We find that dual inhibition of both the mTOR and MAPK pathways by Paxalisib and Mirdametinib synergize to reduce AT/RT growth and viability (Bliss synergy score 16.77). Paxalisib also combines with Mirdametinib to induce high levels of apoptosis and cell senescence (as determined by western blot: cPARP, pRB, P21, P16). Naïve treatments in mice bearing AT/RT orthotopic tumors suggests the combination therapy decrease mTOR and MAPK pathway activation (as determined by western blot). These data support the use of Paxalisib and Mirdametinib combination therapy as a promising novel combination therapy to treat relapsed AT/RT. Citation Format: Kristen J. Malebranche, Tyler Findlay, Anupa Geethadevi, Charles Eberhart, Eric Raabe, Jeffrey Rubens. The PI3K inhibitor Paxalisib combines synergistically with the MEK inhibitor Mirdametinib to target atypical teratoid/rhabdoid tumors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5509.
Abstract 1238: Loss of HSPD1 induces cellular plasticity in triple-negative breast cancer cells
Authors: Muhammad G. Khodary, Alehegne W. Yirsaw, Temesgen Samuel, Clayton Yates, Deepa Bedi
Journal: Cancer Research (2023)

Abstract Abstract Background Unlike Breast cancer (BRCA) luminal subtypes, Triple negative breast cancer (TNBC) subtype lacks expression of estrogen receptor-α (ERα/ESR1), progesterone receptor (PGR) and/or epidermal growth factor (EGF) family receptor HER2/ERBB2 where patients do not benefit from endocrine and HER2 based therapies in addition to its poor differentiation that results in greater aggressiveness and poorer prognosis. The 60 KD Heat shock protein (HSP60) is a Mitochondrial protein that plays a role in stabilizing and refolding proteins and is regulated by HSPD1 gene. In normal cells, HSPD1 gene expression is controlled, however in TNBC, HSPD1 overexpression is common and is associated with poor cancer-specific survival. This study aims to understand downstream signaling pathways dependent on the function of HSPD1 in TNBC. Method To understand downstream signaling pathways dependent on the function of HSPD1, we analyzed the transcriptomic profiles of metastatic MDA-MB-231-WT and HSPD1-KD cells. Results Bioinformatics data analysis shows that HSPD1 is overexpressed in TNBC, particularly in basal subtype. High expression of HSPD1 related to low survival in breast cancer patients. HSPD1 KD in MDA-MB-231 cells identified several differentially regulated genes (DEG) as compared to WT MDA-MB-231 cells by RNA-seq analysis. Pathway analysis of DEG showed downregulation of mitochondrial respiration, thermogenesis, citric acid cycle, PD-1 signaling while upregulation of estrogen dependent gene expression, estrogen mediated signaling, nuclear receptor transcription pathway. These suggests that HSP60 overexpression in TNBC promotes basal type phenotype. Downregulation of HSP60 expression upregulated hormone receptors, particularly estrogen receptor (ESR1) and androgen receptor (AR) expression, thus inducing basal to luminal switch in MDA-MB-231 cells. These findings suggest that loss of HSPD1 significantly Induces plasticity in TNBC. Conclusion Our results suggest that loss of HSPDI in the context TNBC cells may promotes oncogenic transformation to an intermediary luminal progenitor phenotype that gains differentiation plasticity based on the upregulation of Estrogen-receptors signaling pathways. Ongoing analyses will be performed to identify the possible links between loss of HSPD1 and key transcription factors that define mammary epithelial cell differentiation. Citation Format: Muhammad G. Khodary, Alehegne W. Yirsaw, Temesgen Samuel, Clayton Yates, Deepa Bedi. Loss of HSPD1 induces cellular plasticity in triple-negative breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1238.
Abstract 2856: Age-induced chronic accumulation of cortisol drives chemotherapy resistance in lung cancer
Authors: Devesh Raizada, Stanislav Drapela, Joanne Tejero, Nadir Sarigul, Didem Ilter, Ana Gomes
Journal: Cancer Research (2023)

Abstract Lung cancer accounts for the largest number of cancer-associated deaths in the United States. While great strides have been made due to the introduction of immunotherapies and targeted therapies against oncogenic drivers, chemotherapies remain the standard of care for the majority of lung cancer patients. However, many patients do not respond to these treatments or relapse following an initial response. We postulate that part of the problem is the lack of consideration in preclinical research and clinical trials of the main driver of lung tumorigenesis, the aging process. Here, we show that the organismal reprogramming that occurs with aging makes lung tumors in an aged host more conducive to withstand chemotherapies. We traced this to an age-induced chronic accumulation of the stress hormone cortisol in circulation. Mechanistically our data show that chronic accumulation of cortisol drives the upregulation of metallothioneins—small, highly conserved, cysteine-rich metal-binding proteins—through activation of the glucocorticoid receptor in lung cancer cells, which in turn rewire these cells to be refractory to chemotherapies. Together, our work demonstrates a role for age-induced cortisol levels in promoting resistance to standard of care chemotherapies in lung cancer and offers a rationale for using therapeutic agents that block the glucocorticoid receptor to sensitize the average and most vulnerable lung cancer patients, the elderly, to chemotherapy. Citation Format: Devesh Raizada, Stanislav Drapela, Joanne Tejero, Nadir Sarigul, Didem Ilter, Ana Gomes. Age-induced chronic accumulation of cortisol drives chemotherapy resistance in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2856.